The present invention relates to novel cyclic peptide compounds with potent activity against antibiotic-resistant pathogens.
Methicillin-resistant strains of Staphylococcus aureus (USA) cause infections that are refractory to standard anti-staphylococci antibiotics, and in many cases vancomycin is the antibiotic of last resort. Consequently, it is of great concern that vancomycin-resistant strains of MRSA may develop.
Infections due to enterococci have been difficult to treat for many years because these organisms are intrinsically resistant to many antibiotics. Ampicillin has been the mainstay for treatment of uncomplicated enterococcal infections, but many strains have now become resistant to ampicillin. Vancomycin is again the only effective treatment for these ampicillin-resistant enterococcal infections. In the past few years, vancomycin-resistant enterococcal strains (VRE) have begun to appear and they are rapidly spreading across North America. There are no effective antibiotics currently available for such organisms and the recent report of an outbreak of VRE with a 73% mortality rate has highlighted the seriousness of the situation. See Edmond, M. B. et al., Clinical Infectious Diseases 20:1126-33, 1995.
One area where new drugs are desperately needed is in the treatment of antibiotic-resistant strains of gram positive human pathogens. The present invention is directed to fulfilling this need, and provides related advantages as described herein.
In a first aspect, the invention is directed to isolated cyclic decapeptides of the formulas (1), (2) and (3):
(1): cyclo [L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-Asp-L-Tyr] (SEQ ID NO:1);
(2): cyclo [L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:2); and
(3) cyclo [L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:3).
The decapeptide of Formula (1) is referred to herein as Loloatin A. The decapeptide of Formula (2) is referred to herein as Loloatin B. The decapeptide of Formula (3) is referred to herein as Loloatin C.
The invention is directed to the above-identified cyclic decapeptides in an isolated, i.e., substantially purified form, preferably in a quantity of more than about 1 gram, more preferably in a quantity of more than about 10 grams, still more preferably in a quantity of more than about 100 grams, and yet still more preferably in a quantity of more than about 1 kilogram. A substantially purified form is a composition wherein the above-listed cyclic decapeptides constitute at least about 1 weight percent of the composition, preferably at least about 10 weight percent, more preferably at least about 30 weight percent, still more preferably at least about 50 weight percent, yet still more preferably at least about 70 weight percent, and yet still more preferably at least about 95 weight percent, and most preferably at least about 99 weight percent.
The invention is also directed to the above-identified cyclic decapeptides in a pharmaceutical composition. A pharmaceutical composition of the invention may not necessarily contain the cyclic decapeptide in a substantially purified form because the composition may contain diluent and/or other materials commonly found in pharmaceutical compositions.
The invention is also directed to a method of treating bacterial infection, comprising administering to a patient having a bacterial infection, an amount of the above-identified cyclic decapeptides effective to relieve symptoms associated with or due to the bacterial infection.
In another aspect, the invention is directed to various derivatives and analogs of Loloatin A, B and C.
Loloatin derivatives of the invention include the solvates, salts (either acid- or base- addition salts, depending on whether the amino acid sidechain being converted to a salt is basic or acidic, respectively), esters (derivatives of amino acid sidechains containing a carboxylic acid group), amines (derivatives of amino acid sidechains containing an amino group), ethers (derivatives of amino acid sidechains containing an hydroxyl group) and amides (derivatives of amino acid sidechains containing either an amine or carboxylic acid group) of Loloatin A, B or C.
For example, the invention provides for a salt of a compound selected from the group:
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Tyr] (SEQ ID NO:1);
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:2); and
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:3).
The salt may contain at least one negatively charged ion selected from chloride, bromide, sulfate, phosphate, C1-15carboxylate, methanesulfonate and p-toluenesulfonate, which are exemplary only. Exemplary C1-15carboxylates include acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate and 2-phenoxybenzoate.
The salt may contain at least one positively charged ion selected from lithium, sodium, potassium, beryllium, magnesium, calcium and quaternary ammonium ions, which are exemplary positively charged ions. Exemplary quaternary ammonium ions cinlude tetraallylammonium, and trialkylaralkylammonium ions.
The invention also provides for derivatives of a compound selected from
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Tyr] (SEQ ID NO:1);
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Phe-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:2); and
cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-Trp] (SEQ ID NO:3).
For example, the derivative may have the amine group of the ornithine sidechain being a secondary, tertiary or quaternary amine group, and other amino acid sidechains are optionally in a derivative form as well. Exemplary ornithine sidechains have the formula xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94NHR3, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R3)2 or xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94N(R3)3 wherein R3 is an alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an acyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities.
In other derivatives, the hydroxyl group of one or more tyrosine sidechains has been converted to an ether or ester group, and other amino acid sidechains are optionally in a derivative form as well. For example, at least one tyrosine sidechain may have the formula xe2x80x94CH2xe2x80x94C6H4xe2x80x94Oxe2x80x94R2, wherein C6H4 is an aromatic ring and xe2x80x94Oxe2x80x94R2 is in the para position, and R2 is a C1-15 alkyl group so as to form an ether, where the alkyl group may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or a C1-15 acyl group so as to form an ester, where the acyl group may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities.
In other derivatives, the carboxyl group of the aspartic acid sidechain has been converted to an amide or ester group, and other amino acid sidechains are optionally in a derivative form as well. For example, the aspartic acid sidechain may have the formula xe2x80x94CH2xe2x80x94C(xe2x95x90O)Oxe2x80x94R1, and R1 is a C1-15 alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an aryl group. In another example, the aspartic acid sidechain has the formula xe2x80x94CH2xe2x80x94C(xe2x95x90O)Nxe2x80x94R1, and R1 is a C1-15 alkyl group that may be of straight chain, or where possible, of cyclic or branched structure and may contain one or more alkene, alkyne, or aromatic functionalities; or an aryl group.
The invention also provides for a pharmaceutical composition comprising a salt, derivative or analog of any of Loloatin A, Loloatin B and Loloatin C, as set forth above, in admixture with a pharmaceutically acceptable carrier.
The invention also provides for a method for the treatment of a patient afflicted with a bacterial infection comprising the administration to said patient of a therapeutically effective amount of a salt, derivative or analog of any of Loloatin A, Loloatin B and Loloatin C, as set forth above
The invention also provides for the use of a salt, derivative or analog of any of Loloatin A, Loloatin B and Loloatin C, as set forth above, in the manufacture of a medicament, where the medicament may be used to treat bacterial infection.
The Loloatin analogs include cyclic decapeptides having a xe2x80x9cnon-naturalxe2x80x9d stereochemistry at one or more of the xcex1-carbons of the component amino acids, where the xe2x80x9cnaturalxe2x80x9d stereochemistry is as indicated by the L- or D- designations preceding the name of each of the amino acids in the formulas for Loloatin A, B and C set forth above. Collectively, these Loloatin analogs are represented by the formulae:
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-Try] (SEQ ID NO:75);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:76); and
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:77).
Furthermore, the invention is directed to various analogs of the above-identified compounds, where preferred analogs have the formulas listed below. In the below-listed structures, no stereochemistry is designated because the analogs of the invention may have any possible stereochemistry at each atom capable of having more than one stereochemical arrangement of substituents. However, looking at the below listed sequences from left to right as written, preferred analogs have the stereochemistry L-, L-, L-, D-, L-, L-, D-, L-, L- and L-. For example, cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-xcex2-Phenylserine] (SEQ ID NO:74), as written below preferably has the stereochemistry cyclo[L-Val-L-Orn-L-Leu-D-Tyr-L-Pro-L-Trp-D-Phe-L-Asn-L-Asp-L-xcex2-Phenylserine] (SEQ ID NO:74).
Preferred analogs have one amino acid residue present in Loloatin A, B or C replaced with a different amino acid residue. Preferred analogs are:
cyclo[Butyrine-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:4),
cyclo[Butyrine-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:5);
cyclo[Butyrine-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:6);
cyclo[Val-diaminobutyric aicd-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:7);
cyclo[Val diaminobutyric aicd-Leu-Try-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:8);
cyclo[Val-diaminobutyric aicd-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:9);
cyclo[Val-Orn-Isoleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:10);
cyclo[Val-Orn-Isoleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:11);
cyclo[Val-Orn-Isoleucine-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:12);
cyclo[Val-Orn-Alloisoleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:13);
cyclo[Val-Orn-Alloisoleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:14);
cyclo[Val-Orn-Alloisoleucine-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:15);
cyclo[Val-Orn-Norvaline-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:16);
cyclo[Val-Orn-Norvaline-Tyr-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:17);
cyclo[Val-Orn-Norvaline-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:18);
cyclo[Val-Orn-Cyclopropylalanine-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:19);
cyclo[Val-Orn-Cyclopropylalanine-Tyr-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:20);
cyclo[Val-Orn-Cyclopropylalanine-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:21);
cyclo[Val-Orn-Norleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:22);
cyclo[Val-Orn-Norleucine-Try-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:23);
cyclo[Val-Orn-Norleucine-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:24);
cyclo[Val-Orn-Norleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:22);
cyclo[Val-Orn-Norleucine-Tyr-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:23);
cyclo[Val-Orn-Norleucine-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:24);
cyclo[Val-Orn-Leu-p-fluorophenylalamine-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:25);
cyclo[Val-Orn-Leu-p-fluorophenylalamine-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:26);
cyclo[Val-Orn-Leu-p-fluorophenylalamine-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:27);
cyclo[Val-Orn-Leu-Tryptophan-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:28);
cyclo[Val-Orn-Leu-Tryptophan-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:29);
cyclo[Val-Orn-Leu-Tryptophan-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:30);
cyclo[Val-Orn-Leu-Thienylalanine-Pro-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:31);
cyclo[Val-Orn-Leu-Thienylalanine-Pro-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:32);
cyclo[Val-Orn-Leu-Thienylalanine-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:33);
cyclo[Val-Orn-Leu-Tyr-Azetidine-2-carboxylic acid-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:34);
cyclo[Val-Orn-Leu-Tyr-Azetidine-2-carboxylic acid-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:35);
cyclo[Val-Orn-Leu-Tyr-Azetidine-2-carboxylic acid-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:36);
cyclo[Val-Orn-Leu-Tyr-Pipecolic acid-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:37);
cyclo[Val-Orn-Leu-Tyr-Pipecolic acid-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:38);
cyclo[Val-Orn-Leu-Tyr-Pipecolic acid-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:39);
cyclo[Val-Orn-Leu-Tyr-trans-3-Methylproline-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:40);
cyclo[Val-Orn-Leu-Tyr-trans-3-Methylproline-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:41);
cyclo[Val-Orn-Leu-Tyr-trans-3-Methylproline-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:42);
cyclo[Val-Orn-Leu-Tyr-trans-4-Fluoroproline-Phe-Phe-Asn-Asp-Tyr] (SEQ ID NO:43);
cyclo[Val-Orn-Leu-Tyr-trans-4-Fluoroproline-Phe-Phe-Asn-Asp-Trp] (SEQ ID NO:44); 
cyclo[Val-Orn-Leu-Tyr-trans-4-Fluoroproline-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:45);
cyclo[Val-Orn-Leu-Tyr-Pro-Tyr-Phe-Asn-Asp-Tyr] (SEQ ID NO:46);
cyclo[Val-Orn-Leu-Tyr-Pro-Tyr-Pher-Asn-Asp-Trp] (SEQ ID NO:47);
cyclo[Val-Orn-Leu-Tyr-Pro-p-Fluorophenylalanine-Phe-Asn-Asp-Tyr] (SEQ ID NO:48);
cyclo[Val-Orn-Leu-Tyr-Pro-p-Fluorophenylalanine-Phe-Asn-Asp-Trp] (SEQ ID NO:49);
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Tyr] (SEQ ID NO:50);
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Trp] (SEQ ID NO:51);
cyclo[Val-Orn-Leu-Tyr-Pro-Thienylalanine-Phe-Asn-Asp-Tyr] (SEQ ID NO:52)
cyclo[Val-Orn-Leu-Tyr-Pro-Thienylalanine-Phe-Asn-Asp-Trp] (SEQ ID NO:53)
cyclo[Val-Orn-Leu-Tyr-Pro-xcex2-Phenylserine-Phe-Asn-Asp-Tyr] (SEQ ID NO:54);
cyclo[Val-Orn-Leu-Tyr-Pro-xcex2-Phenylserine-Phe-Asn-Asp-Trp] (SEQ ID NO:55);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Tyr-Asn-Asp-Tyr] (SEQ ID NO:56);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Tyr-Asn-Asp-Trp] (SEQ ID NO:57);
cyclo[Val-Orn-Leu-Try-Phe-p-Fluorophenylalanine-Asn-Asp-Tyr] (SEQ ID NO:58);
cyclo[Val-Orn-Leu-Try-Phe-p-Fluorophenylalanine-Asn-Asp-Trp] (SEQ ID NO:59);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Trp-Asn-Asp-Tyr] (SEQ ID NO:60);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Trp-Asn-Asp-Trp] (SEQ ID NO:61);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Thienylalanine-Asn-Asp-Tyr] (SEQ ID NO:62);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Thienylalanine-Asn-Asp-Trp] (SEQ ID NO:63);
cyclo[Val-Orn-Leu-Try-Pro-Phe-xcex2-Phenylserine-Asn-Asp-Tyr] (SEQ ID NO:64);
cyclo[Val-Orn-Leu-Try-Pro-Phe-xcex2-Phenylserine-Asn-Asp-Trp] (SEQ ID NO:65);
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Tyr] (SEQ ID NO:66);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-p-Fluorophenylalanine] (SEQ ID NO:67);
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-p-Fluorophenylalanine] (SEQ ID NO:68);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Phe Asn-Asp-Phe] (SEQ ID NO:69);
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Phe] (SEQ ID NO:70);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-Thienylalanine] (SEQ ID NO:71);
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-Thienylalanine] (SEQ ID NO:72);
cyclo[Val-Orn-Leu-Tyr-Pro-Phe-Phe-Asn-Asp-xcex2-Phenylserine] (SEQ ID NO:73); and
cyclo[Val-Orn-Leu-Tyr-Pro-Trp-Phe-Asn-Asp-xcex2-Phenylserine] (SEQ ID NO:73).
The present invention is also directed to derivatives of the above-listed Loloatin analogs (i.e., analog derivatives), including the solvates, salts (either acid- or base- addition salts, depending on whether the amino acid sidechain being converted to a salt is basic or acidic, respectively), esters (derivatives of amino acid sidechains containing a carboxylic acid group), amine (derivatives of amino acid sidechains containing an amino group), ethers (derivatives of amino acid sidechains containing an hydroxyl group) and amides (derivatives of amino acid sidechains containing either an amine or carboxylic acid group) of the Loloatin A, B and C analogs listed above.
Collectively, the above-identified Loloatin A, B and C derivatives, analogs and analog derivatives are referred to herein as compounds of Formula (A), or compounds of the invention.
The invention is also directed to the compounds of the invention in an isolated, i.e., substantially purified form, preferably in a quantity of more than about 1 gram, more preferably in a quantity of more than about 10 grams, still more preferably in a quantity of more than about 100 grams, and yet still more preferably in a quantity of more than about 1 kilogram. A substantially purified form is a composition wherein the above-listed compound of the invention constitutes at least about 1 weight percent of the composition, preferably at least about 10 weight percent, more preferably at least about 30 weight percent, still more preferably at least about 50 weight percent, yet still more preferably at least about 70 weight percent, and yet still more preferably at least about 95 weight percent, and most preferably at least about 99 weight percent.
The invention is also directed to pharmaceutical compositions comprising compounds of the invention.
The invention is also directed to a method of treating bacterial infection, comprising administering to a patient having a bacterial infection, an amount of a compound of the invention effective to relieve symptoms associated with or due to the bacterial infection.
The compounds of the present invention contain multiple asymmetric carbon atoms and thus exist as enantiomers and diastereomers. Unless otherwise noted, the present invention includes all enantiomeric and diastereomeric forms of the compounds. Pure stereoisomers, mixtures of enantiomers and/or diastereomers, and mixtures of different compounds of the invention are included within the scope of the present invention.
The synthesis procedures described herein, especially when taken with the general knowledge in the art, provide sufficient guidance to those of ordinary skill in the art to perform the synthesis, isolation, and purification of the compounds described herein and other analogous compounds. Individual enantiomers may be obtained, if desired, from mixtures of the different forms by known methods of resolution, such as the formation of diastereomers, followed by recrystalisation. Alternatively, isomerically pure starting materials may be employed in the synthesis of a compound of the invention.
The compounds of the invention may be in the form of a solvate or a pharmaceutically acceptable salt, e.g., an acid- or base- addition salt. Such salts may have at least one negatively charged ion such as chloride, bromide, sulfate, phosphate, C1-15carboxylate, methanesulfonate and p-toluenesulfonate, where exemplary C1-15carboxylate ions are acetate, glycolate, lactate, pyruvate, malonate, succinate, glutarate, fumarate, malate, tartarate, citrate, ascorbate, maleate, hydroxymaleate, benzoate, hydroxybenzoate, phenylacetate, cinnamate, salicylate and 2-phenoxybenzoate. The salt may have at least one positively charged ion such as lithium, sodium, potassium, beryllium, magnesium, calcium and quaternary ammonium ions, where exemplary quaternary ammonium ions are tetraalkylammonium, and trialkylaralkylammonium ions.
The invention is also directed to the above-identified cyclic decapeptides and derivatives thereof in a pharmaceutical composition. A pharmaceutical composition of the invention may not necessarily contain the cyclic decapeptide or derivative thereof in a substantially purified form because the composition may contain diluent and/or other materials commonly found in pharmaceutical compositions, such that the above-identified cyclic decapeptides and derivatives thereof constitute less that 1 weight percent of the pharmaceutical composition.
The invention is also directed to a method of employing the compounds of the invention as an antibiotic.